tbuckley/cabot-search huggingface dataset:
Heterozygous <i>BRCA1</i> and <i>BRCA2</i> and Mismatch Repair Gene Pathogenic Variants in Children and Adolescents With Cancer
Authors: Christian P Kratz, Dmitrii Smirnov, Robert Autry, Natalie Jäger, Sebastian M Waszak, Anika Großhennig, Riccardo Berutti, Mareike Wendorff, Pierre Hainaut, Stefan M Pfister, Holger Prokisch, Tim Ripperger, David Malkin
Journal: JNCI Journal of the National Cancer Institute (2022)

Abstract Background Genetic predisposition is has been identified as a cause of cancer, yet little is known about the role of adult cancer predisposition syndromes in childhood cancer. We examined the extent to which heterozygous pathogenic germline variants in BRCA1, BRCA2, PALB2, ATM, CHEK2, MSH2, MSH6, MLH1, and PMS2 contribute to cancer risk in children and adolescents. Methods We conducted a meta-analysis of 11 studies that incorporated comprehensive germline testing for children and adolescents with cancer. ClinVar pathogenic or likely pathogenic variants (PVs) in genes of interest were compared with 2 control groups. Results were validated in a cohort of mainly European patients and controls. We employed the Proxy External Controls Association Test to account for different pipelines. Results Among 3975 children and adolescents with cancer, statistically significant associations with cancer risk were observed for PVs in BRCA1 and 2 (26 PVs vs 63 PVs among 27 501 controls, odds ratio = 2.78, 95% confidence interval = 1.69 to 4.45; P &amp;lt; .001) and mismatch repair genes (19 PVs vs 14 PVs among 27 501 controls, odds ratio = 7.33, 95% confidence interval = 3.64 to 14.82; P &amp;lt;.001). Associations were seen in brain and other solid tumors but not in hematologic neoplasms. We confirmed similar findings in 1664 pediatric cancer patients primarily of European descent. Conclusion These data suggest that heterozygous PVs in BRCA1 and 2 and mismatch repair genes contribute with reduced penetrance to cancer risk in children and adolescents. No changes to predictive genetic testing and surveillance recommendations are required.
Ocular involvement in monkeypox: Description of an unusual presentation during the current outbreak
Authors: V Mazzotta, A Mondi, F Carletti, F Baldini, R Santoro, S Meschi, M Moccione, S Gebremeskel Teklè, C Minosse, M Camici, S Vita, G Matusali, E Nicastri, E Girardi, F Maggi, F Vaia, A Antinori, C Pinnetti
Journal: Journal of Infection (2022)
FOXI3 haploinsufficiency contributes to low T-cell receptor excision circles and T-cell lymphopenia
Authors: Rajarshi Ghosh, Marita Bosticardo, Sunita Singh, Morgan Similuk, Ottavia M Delmonte, Francesca Pala, Christine Peng, Colleen Jodarski, Michael D Keller, Ivan K Chinn, Andrew K Groves, Luigi D Notarangelo, Magdalena A Walkiewicz, Javier Chinen, Vanessa Bundy
Journal: Journal of Allergy and Clinical Immunology (2022)
Intrapartum use of zidovudine in a large cohort of pregnant women living with HIV in Italy
Authors: Lucia Taramasso, Francesca Bovis, Antonio Di Biagio, Federica Mignone, Carlo Giaquinto, Claudia Tagliabue, Vania Giacomet, Orazio Genovese, Elena Chiappini, Serena Salomè, Raffaele Badolato, Ines Carloni, Monica Cellini, Icilio Dodi, Grazia Bossi, Alessandra Allodi, Stefania Bernardi, Rita Consolini, Maurizio Dedoni, Giuseppe Banderali, Antonio Mazza, Giulia Pruccoli, Osvalda Rampon, Paola Erba, Giada Di Pietro, Carlotta Montagnani, Letizia Capasso, Laura Dotta, Federica Zallocco, Maurizio De Martino, Catiuscia Lisi, Pier Angelo Tovo, Matteo Bassetti, Clara Gabiano, Luisa Galli
Journal: Journal of Infection (2022)
Unconventional Oil and Gas Development Exposure and Risk of Childhood Acute Lymphoblastic Leukemia: A Case–Control Study in Pennsylvania, 2009–2017
Authors: Cassandra J. Clark, Nicholaus P. Johnson, Mario Soriano, Joshua L. Warren, Keli M. Sorrentino, Nina S. Kadan-Lottick, James E. Saiers, Xiaomei Ma, Nicole C. Deziel
Journal: Environmental Health Perspectives (2022)

Background: Unconventional oil and gas development (UOGD) releases chemicals that have been linked to cancer and childhood leukemia. Studies of UOGD exposure and childhood leukemia are extremely limited. Objective: The objective of this study was to evaluate potential associations between residential proximity to UOGD and risk of acute lymphoblastic leukemia (ALL), the most common form of childhood leukemia, in a large regional sample using UOGD-specific metrics, including a novel metric to represent the water pathway. Methods: We conducted a registry-based case–control study of 405 children ages 2–7 y diagnosed with ALL in Pennsylvania between 2009–2017, and 2,080 controls matched on birth year. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between residential proximity to UOGD (including a new water pathway-specific proximity metric) and ALL in two exposure windows: a primary window (3 months preconception to 1 y prior to diagnosis/reference date) and a perinatal window (preconception to birth). Results: Children with at least one UOG well within 2km of their birth residence during the primary window had 1.98 times the odds of developing ALL in comparison with those with no UOG wells [95% confidence interval (CI): 1.06, 3.69]. Children with at least one vs. no UOG wells within 2km during the perinatal window had 2.80 times the odds of developing ALL (95% CI: 1.11, 7.05). These relationships were slightly attenuated after adjusting for maternal race and socio-economic status [odds ratio (OR) =1.74 (95% CI: 0.93, 3.27) and OR=2.35 (95% CI: 0.93, 5.95)], respectively). The ORs produced by models using the water pathway-specific metric were similar in magnitude to the aggregate metric. Discussion: Our study including a novel UOGD metric found UOGD to be a risk factor for childhood ALL. This work adds to mounting evidence of UOGD's impacts on children's health, providing additional support for limiting UOGD near residences. https://doi.org/10.1289/EHP11092
Utilization of elderly donors in liver transplantation for patients with hepatocellular carcinoma: A national retrospective cohort study of China
Authors: Liangshuo Hu, Zhen Zhao, Fan Mu, Siyi Dong, Chun Zhang, Jianhua Shi, Min Tian, Kun Guo, Xufeng Zhang, Liang Yu, Yi Lv, Bo Wang
Journal: International Journal of Surgery (2022)
The pre-exposure SARS-CoV-2-specific T cell repertoire determines the quality of the immune response to vaccination
Authors: Carina Saggau, Gabriela Rios Martini, Elisa Rosati, Silja Meise, Berith Messner, Ann-Kristin Kamps, Nicole Bekel, Johannes Gigla, Ruben Rose, Mathias Voß, Ulf M. Geisen, Hayley M. Reid, Melike Sümbül, Florian Tran, Dennis K. Berner, Yascha Khodamoradi, Maria J.G.T. Vehreschild, Oliver Cornely, Philipp Koehler, Andi Krumbholz, Helmut Fickenscher, Oliver Kreuzer, Claudia Schreiber, Andre Franke, Stefan Schreiber, Bimba Hoyer, Alexander Scheffold, Petra Bacher
Journal: Immunity (2022)
Mesenchymal stromal cells improve the transplantation outcome of CRISPR-Cas9 gene-edited human HSPCs
Authors: Stefania Crippa, Anastasia Conti, Valentina Vavassori, Samuele Ferrari, Stefano Beretta, Silvia Rivis, Roberto Bosotti, Serena Scala, Stefania Pirroni, Raisa Jofra-Hernandez, Ludovica Santi, Luca Basso-Ricci, Ivan Merelli, Pietro Genovese, Alessandro Aiuti, Luigi Naldini, Raffaella Di Micco, Maria Ester Bernardo
Journal: Molecular Therapy (2022)

Mesenchymal stromal cells (MSCs) have been employed in vitro to support hematopoietic stem and progenitor cell (HSPC) expansion and in vivo to promote HSPC engraftment. Based on these studies, we developed an MSC-based co-culture system to optimize the transplantation outcome of clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 gene-edited (GE) human HSPCs. We show that bone marrow (BM)-MSCs produce several hematopoietic supportive and anti-inflammatory factors capable of alleviating the proliferation arrest and mitigating the apoptotic and inflammatory programs activated in GE-HSPCs, improving their expansion and clonogenic potential in vitro. The use of BM-MSCs resulted in superior human engraftment and increased clonal output of GE-HSPCs contributing to the early phase of hematological reconstitution in the peripheral blood of transplanted mice. In conclusion, our work poses the biological bases for a novel clinical use of BM-MSCs to promote engraftment of GE-HSPCs and improve their transplantation outcome.
The short-term effects of opioid and non-opioid pharmacotherapies on sleep in people with chronic low back pain: A systematic review and meta-analysis of randomized controlled trials
Authors: James M. Puterflam, Julian J. Comis, Qianwen Lan, Chen Liu, Adam J. Lipschitz, Ronald R. Grunstein, Paulo H. Ferreira, Christopher J. Gordon
Journal: Sleep Medicine Reviews (2022)
BH3 mimetics targeting BCL-XL impact the senescent compartment of pilocytic astrocytoma
Authors: Florian Selt, Romain Sigaud, Gintvile Valinciute, Philipp Sievers, Julia Zaman, Clara Alcon, Simone Schmid, Heike Peterziel, Jessica W Tsai, Romain Guiho, Juan Pedro Martínez-Barbera, Stefan Pusch, Jing Deng, Yifan Zhai, Cornelis M van Tilburg, Martin U Schuhman, Ahmed El Damaty, Pratiti Bandopadhayay, Christel Herold-Mende, Andreas von Deimling, Stefan M Pfister, Joan Montero, David Capper, Ina Oehme, Felix Sahm, David T W Jones, Olaf Witt, Till Milde
Journal: Neuro-Oncology (2022)

Abstract Background Pilocytic astrocytoma (PA) is the most common pediatric brain tumor and a mitogen-activated protein kinase (MAPK)-driven disease. Oncogenic MAPK-signaling drives the majority of cells into oncogene-induced senescence (OIS). While OIS induces resistance to antiproliferative therapies, it represents a potential vulnerability exploitable by senolytic agents. Methods We established new patient-derived PA cell lines that preserve molecular features of the primary tumors and can be studied in OIS and proliferation depending on expression or repression of the SV40 large T antigen. We determined expression of anti-apoptotic BCL-2 members in these models and primary PA. Dependence of senescent PA cells on anti-apoptotic BCL-2 members was investigated using a comprehensive set of BH3 mimetics. Results Senescent PA cells upregulate BCL-XL upon senescence induction and show dependency on BCL-XL for survival. BH3 mimetics with high affinity for BCL-XL (BCL-XLi) reduce metabolic activity and induce mitochondrial apoptosis in senescent PA cells at nano-molar concentrations. In contrast, BH3 mimetics without BCL-XLi activity, conventional chemotherapy, and MEK inhibitors show no effect. Conclusions Our data demonstrate that BCL-XL is critical for survival of senescent PA tumor cells and provides proof-of-principle for the use of clinically available BCL-XL-dependent senolytics.
Mutations of TRPM8 channels: Unraveling the molecular basis of activation by cold and ligands
Authors: Alejandro Plaza‐Cayón, Rosario González‐Muñiz, Mercedes Martín‐Martínez
Journal: Medicinal Research Reviews (2022)

The cation nonselective channel TRPM8 is activated by multiple stimuli, including moderate cold and various chemical compounds (i.e., menthol and icilin [Fig. 1], among others). While research continues growing on the understanding of the physiological involvement of TRPM8 channels and their role in various pathological states, the information available on its activation mechanisms has also increased, supported by mutagenesis and structural studies. This review compiles known information on specific mutations of channel residues and their consequences on channel viability and function. Besides, the comparison of sequence of animals living in different environments, together with chimera and mutagenesis studies are helping to unravel the mechanism of adaptation to different temperatures. The results of mutagenesis studies, grouped by different channel regions, are compared with the current knowledge of TRPM8 structures obtained by cryo-electron microscopy. Trying to make this review self-explicative and highly informative, important residues for TRPM8 function are summarized in a figure, and mutants, deletions and chimeras are compiled in a table, including also the observed effects by different methods of activation and the corresponding references. The information provided by this review may also help in the design of new ligands for TRPM8, an interesting biological target for therapeutic intervention.
Stratifying the autistic phenotype using electrophysiological indices of social perception
Authors: Luke Mason, Carolin Moessnang, Christopher Chatham, Lindsay Ham, Julian Tillmann, Guillaume Dumas, Claire Ellis, Claire S. Leblond, Freddy Cliquet, Thomas Bourgeron, Christian Beckmann, Tony Charman, Beth Oakley, Tobias Banaschewski, Andreas Meyer-Lindenberg, Simon Baron-Cohen, Sven Bölte, Jan K. Buitelaar, Sarah Durston, Eva Loth, Bob Oranje, Antonio Persico, Flavio Dell’Acqua, Christine Ecker, Mark H. Johnson, Declan Murphy, Emily J. H. Jones
Journal: Science Translational Medicine (2022)

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by difficulties in social communication, but also great heterogeneity. To offer individualized medicine approaches, we need to better target interventions by stratifying autistic people into subgroups with different biological profiles and/or prognoses. We sought to validate neural responses to faces as a potential stratification factor in ASD by measuring neural (electroencephalography) responses to faces (critical in social interaction) in N = 436 children and adults with and without ASD. The speed of early-stage face processing (N170 latency) was on average slower in ASD than in age-matched controls. In addition, N170 latency was associated with responses to faces in the fusiform gyrus, measured with functional magnetic resonance imaging, and polygenic scores for ASD. Within the ASD group, N170 latency predicted change in adaptive socialization skills over an 18-month follow-up period; data-driven clustering identified a subgroup with slower brain responses and poor social prognosis. Use of a distributional data-driven cutoff was associated with predicted improvements of power in simulated clinical trials targeting social functioning. Together, the data provide converging evidence for the utility of the N170 as a stratification factor to identify biologically and prognostically defined subgroups in ASD.
Sphingosine 1-phosphate signaling in perivascular cells enhances inflammation and fibrosis in the kidney
Authors: Shinji Tanaka, Shuqiu Zheng, Yugesh Kharel, Russell G. Fritzemeier, Tao Huang, Daniel Foster, Nabin Poudel, Eibhlin Goggins, Yusuke Yamaoka, Kinga P. Rudnicka, Jonathan E. Lipsey, Hope V. Radel, Sophia M. Ryuh, Tsuyoshi Inoue, Junlan Yao, Diane L. Rosin, Susan R. Schwab, Webster L. Santos, Kevin R. Lynch, Mark D. Okusa
Journal: Science Translational Medicine (2022)

Chronic kidney disease (CKD), characterized by sustained inflammation and progressive fibrosis, is highly prevalent and can eventually progress to end-stage kidney disease. However, current treatments to slow CKD progression are limited. Sphingosine 1-phosphate (S1P), a product of sphingolipid catabolism, is a pleiotropic mediator involved in many cellular functions, and drugs targeting S1P signaling have previously been studied particularly for autoimmune diseases. The primary mechanism of most of these drugs is functional antagonism of S1P receptor-1 (S1P1) expressed on lymphocytes and the resultant immunosuppressive effect. Here, we documented the role of local S1P signaling in perivascular cells in the progression of kidney fibrosis using primary kidney perivascular cells and several conditional mouse models. S1P was predominantly produced by sphingosine kinase 2 in kidney perivascular cells and exported via spinster homolog 2 (Spns2). It bound to S1P1 expressed in perivascular cells to enhance production of proinflammatory cytokines/chemokines upon injury, leading to immune cell infiltration and subsequent fibrosis. A small-molecule Spns2 inhibitor blocked S1P transport, resulting in suppression of inflammatory signaling in human and mouse kidney perivascular cells in vitro and amelioration of kidney fibrosis in mice. Our study provides insight into the regulation of inflammation and fibrosis by S1P and demonstrates the potential of Spns2 inhibition as a treatment for CKD and potentially other inflammatory and fibrotic diseases that avoids the adverse events associated with systemic modulation of S1P receptors.
Black phosphorus nanosheets-enabled DNA hydrogel integrating 3D-printed scaffold for promoting vascularized bone regeneration
Authors: Yali Miao, Yunhua Chen, Jinshui Luo, Xiao Liu, Qian Yang, Xuetao Shi, Yingjun Wang
Journal: Bioactive Materials (2022)

The classical 3D-printed scaffolds have attracted enormous interests in bone regeneration due to the customized structural and mechanical adaptability to bone defects. However, the pristine scaffolds still suffer from the absence of dynamic and bioactive microenvironment that is analogous to natural extracellular matrix (ECM) to regulate cell behaviour and promote tissue regeneration. To address this challenge, we develop a black phosphorus nanosheets-enabled dynamic DNA hydrogel to integrate with 3D-printed scaffold to build a bioactive gel-scaffold construct to achieve enhanced angiogenesis and bone regeneration. The black phosphorus nanosheets reinforce the mechanical strength of dynamic self-healable hydrogel and endow the gel-scaffold construct with preserved protein binding to achieve sustainable delivery of growth factor. We further explore the effects of this activated construct on both human umbilical vein endothelial cells (HUVECs) and mesenchymal stem cells (MSCs) as well as in a critical-sized rat cranial defect model. The results confirm that the gel-scaffold construct is able to promote the growth of mature blood vessels as well as induce osteogenesis to promote new bone formation, indicating that the strategy of nano-enabled dynamic hydrogel integrated with 3D-printed scaffold holds great promise for bone tissue engineering.
Planar‐/Curvilinear‐Bioprinted Tri‐Cell‐Laden Hydrogel for Healing Irregular Chronic Wounds (Adv. Healthcare Mater. 16/2022)
Authors: Shin‐Da Wu, Niann‐Tzyy Dai, Chao‐Yaug Liao, Lan‐Ya Kang, Yu‐Wen Tseng, Shan‐hui Hsu
Journal: Advanced Healthcare Materials (2022)

Wound Healing In article 2201021 by Shan-hui Hsu and co-workers, irregular skin wounds of diabetic rats covered with a curvilinear-bioprinted tri-cell-laden hydrogel containing allogeneic fibroblasts, keratinocytes, and endothelial progenitor cells can recover with full epithelialization and collagen production, which represents a potential new technology for treating chronic wounds.
Coaxially Fabricated Dual‐Drug Loading Electrospinning Fibrous Mat with Programmed Releasing Behavior to Boost Vascularized Bone Regeneration (Adv. Healthcare Mater. 16/2022)
Authors: Jinjie Cui, Xingge Yu, Bin Yu, Xiuyi Yang, Zeyu Fu, Jianyu Wan, Min Zhu, Xudong Wang, Kaili Lin
Journal: Advanced Healthcare Materials (2022)
Vaccine effectiveness of BNT162b2 and CoronaVac against SARS-CoV-2 Omicron BA.2 infection, hospitalisation, severe complications, cardiovascular disease and mortality in patients with diabetes mellitus: A case control study
Authors: Eric Yuk Fai Wan, Anna Hoi Ying Mok, Vincent Ka Chun Yan, Boyuan Wang, Ran Zhang, Sabrina Nan Hong, Celine Sze Ling Chui, Xue Li, Carlos King Ho Wong, Francisco Tsz Tsun Lai, Kathryn Choon Beng Tan, Chak Sing Lau, Ian Chi Kei Wong, Esther Wai Yin Chan
Journal: Journal of Infection (2022)
Widespread cell stress and mitochondrial dysfunction occur in patients with early Alzheimer’s disease
Authors: Ashwin V. Venkataraman, Ayla Mansur, Gaia Rizzo, Courtney Bishop, Yvonne Lewis, Ece Kocagoncu, Anne Lingford-Hughes, Mickael Huiban, Jan Passchier, James B. Rowe, Hideo Tsukada, David J. Brooks, Laurent Martarello, Robert A. Comley, Laigao Chen, Adam J. Schwarz, Richard Hargreaves, Roger N. Gunn, Eugenii A. Rabiner, Paul M. Matthews
Journal: Science Translational Medicine (2022)

Cell stress and impaired oxidative phosphorylation are central to mechanisms of synaptic loss and neurodegeneration in the cellular pathology of Alzheimer’s disease (AD). In this study, we quantified the in vivo expression of the endoplasmic reticulum stress marker, sigma 1 receptor (S1R), using [ 11 C]SA4503 positron emission tomography (PET), the mitochondrial complex I (MC1) with [ 18 F]BCPP-EF, and the presynaptic vesicular protein SV2A with [ 11 C]UCB-J in 12 patients with early AD and in 16 cognitively normal controls. We integrated these molecular measures with assessments of regional brain volumes and cerebral blood flow (CBF) measured with magnetic resonance imaging arterial spin labeling. Eight patients with AD were followed longitudinally to estimate the rate of change of the physiological and structural pathology markers with disease progression. The patients showed widespread increases in S1R (≤ 27%) and regional reduction in MC1 (≥ −28%) and SV2A (≥ −25%) radioligand binding, brain volume (≥ −23%), and CBF (≥ −26%). [ 18 F]BCPP-EF PET MC1 binding (≥ −12%) and brain volumes (≥ −5%) showed progressive reductions over 12 to 18 months, suggesting that they both could be used as pharmacodynamic indicators in early-stage therapeutics trials. Associations of reduced MC1 and SV2A and increased S1R radioligand binding with reduced cognitive performance in AD, although exploratory, suggested a loss of metabolic functional reserve with disease. Our study thus provides in vivo evidence for widespread, clinically relevant cellular stress and bioenergetic abnormalities in early AD.
ER stress and inflammation crosstalk in obesity
Authors: Amir Ajoolabady, Cynthia Lebeaupin, Ne N. Wu, Randal J. Kaufman, Jun Ren
Journal: Medicinal Research Reviews (2022)

Abstract The endoplasmic reticulum (ER) governs the proper folding of polypeptides and proteins through various chaperones and enzymes residing within the ER organelle. Perturbation in the ER folding process ensues when overwhelmed protein folding exceeds the ER handling capacity, leading to the accumulation of misfolded/unfolded proteins in the ER lumen—a state being referred to as ER stress. In turn, ER stress induces a gamut of signaling cascades, termed as the “unfolded protein response” (UPR) that reinstates the ER homeostasis through a panel of gene expression modulation. This type of UPR is usually deemed “adaptive UPR.” However, persistent or unresolved ER stress hyperactivates UPR response, which ultimately, triggers cell death and inflammatory pathways, termed as “maladaptive/terminal UPR.” A plethora of evidence indicates that crosstalks between ER stress (maladaptive UPR) and inflammation precipitate obesity pathogenesis. In this regard, the acquisition of the mechanisms linking ER stress to inflammation in obesity might unveil potential remedies to tackle this pathological condition. Herein, we aim to elucidate key mechanisms of ER stress‐induced inflammation in the context of obesity and summarize potential therapeutic strategies in the management of obesity through maneuvering ER stress and ER stress‐associated inflammation.